Dataset Information

Infectivity-Enhanced, Conditionally Replicative Adenovirus for COX-2-Expressing Castration-Resistant Prostate Cancer.

ABSTRACT:

Background

The development of conditionally replicative adenoviruses (CRAds) for castration-resistant prostate cancer (CRPC), particularly neuroendocrine prostate cancer (NEPC), has two major obstacles: choice of control element and poor infectivity. We applied fiber-modification-based infectivity enhancement and an androgen-independent promoter (cyclooxynegase-2, COX-2) to overcome these issues.

Methods

The properties of the COX-2 promoter and the effect of fiber modification were tested in two CRPC cell lines (Du-145 and PC3). Fiber-modified COX-2 CRAds were tested in vitro for cytocidal effect as well as in vivo for antitumor effect with subcutaneous CRPC xenografts.

Results

In both CRPC cell lines, the COX-2 promoter showed high activity, and Ad5/Ad3 fiber modification significantly enhanced adenoviral infectivity. COX-2 CRAds showed a potent cytocidal effect in CRPC cells with remarkable augmentation by fiber modification. In vivo, COX-2 CRAds showed an antitumor effect in Du-145 while only Ad5/Ad3 CRAd showed the strongest antitumor effect in PC3.

Conclusion

COX-2 promoter-based, infectivity-enhanced CRAds showed a potent antitumor effect in CRPC/NEPC cells.

SUBMITTER: Gavrikova T

PROVIDER: S-EPMC10144787 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Infectivity-Enhanced, Conditionally Replicative Adenovirus for COX-2-Expressing Castration-Resistant Prostate Cancer.

Gavrikova Tatyana T Nakamura Naohiko N Davydova Julia J Antonarakis Emmanuel S ES Yamamoto Masato M

Viruses 20230331 4

<h4>Background</h4>The development of conditionally replicative adenoviruses (CRAds) for castration-resistant prostate cancer (CRPC), particularly neuroendocrine prostate cancer (NEPC), has two major obstacles: choice of control element and poor infectivity. We applied fiber-modification-based infectivity enhancement and an androgen-independent promoter (cyclooxynegase-2, COX-2) to overcome these issues.<h4>Methods</h4>The properties of the COX-2 promoter and the effect of fiber modification wer ...[more]

PMID: 37112881

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Project description:In view of the limited success of available treatment modalities for a wide array of cancer, alternative and complementary therapeutic strategies need to be developed. Virotherapy employing conditionally replicative adenoviruses (CRAds) represents a promising targeted intervention relevant to a wide array of neoplastic diseases. Critical to the realization of an acceptable therapeutic index using virotherapy in clinical trials is the achievement of oncolytic replication in tumor cells, while avoiding non-specific replication in normal tissues. In this report, we exploited cancer-specific control of mRNA translation initiation in order to achieve enhanced replicative specificity of CRAd virotherapy agents. Heretofore, the achievement of replicative specificity of CRAd agents has been accomplished either by viral genome deletions or incorporation of tumor selective promoters. In contrast, control of mRNA translation has not been exploited for the design of tumor specific replicating viruses to date. We show herein, the utility of a novel approach that combines both transcriptional and translational regulation strategies for the key goal of replicative specificity.We describe the construction of a CRAd with cancer specific gene transcriptional control using the CXCR4 gene promoter (TSP) and cancer specific mRNA translational control using a 5'-untranslated region (5'-UTR) element from the FGF-2 (Fibroblast Growth Factor-2) mRNA.Both in vitro and in vivo studies demonstrated that our CRAd agent retains anti-tumor potency. Importantly, assessment of replicative specificity using stringent tumor and non-tumor tissue slice systems demonstrated significant improvement in tumor selectivity.Our study addresses a conceptually new paradigm: dual targeting of transgene expression to cancer cells using both transcriptional and mRNA translational control. Our novel approach addresses the key issue of replicative specificity and can potentially be generalized to a wide array of tumor types, whereby tumor selective patterns of gene expression and mRNA translational control can be exploited.

Dataset Information

Infectivity-Enhanced, Conditionally Replicative Adenovirus for COX-2-Expressing Castration-Resistant Prostate Cancer.

Background

Methods

Results

Conclusion

Publications

Infectivity-Enhanced, Conditionally Replicative Adenovirus for COX-2-Expressing Castration-Resistant Prostate Cancer.

Similar Datasets

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